Ly6Chi Monocytes Direct Alternatively Activated Profibrotic Macrophage Regulation of Lung Fibrosis
Ly6Chi Monocytes Direct Alternatively Activated Profibrotic Macrophage Regulation of Lung Fibrosis
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DOI：
10.1164/rccm.201010-1719oc
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发表时间：
2011-09-01
影响因子：
24.7
通讯作者：
Forbes, Stuart J.
中科院分区：
文献类型：
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作者：
Gibbons, Michael A.;MacKinnon, Alison C.;Forbes, Stuart J.
原理：特发性肺纤维化（IPF）是一种破坏性疾病。抗炎治疗，包括皮质类固醇，是没有好处的。因此，单核细胞和巨噬细胞的作用是有争议的。Objective. Objectives：为了定义肺纤维化和决议过程中的单核细胞和巨噬细胞的作用，并探讨表型的细胞involved.Methods：我们使用了多种体内消耗策略，支持过继转移技术。测量和主要结果：在纤维形成过程中肺巨噬细胞的消耗减少了肺纤维化，如肺胶原蛋白测定的，（P = 0.0079）;纤维化评分（P = 0.0051）;定量聚合酶链反应检测纤维化替代标志物Col 1（P = 0.0083）和α-平滑肌肌动蛋白（P = 0.0349）。促纤维化替代巨噬细胞活化表型标志物Ym 1（P = 0.0179）和精氨酸酶1相关减少。另一种巨噬细胞标志物CD 163在IPF患者的肺巨噬细胞上表达。Ly 6C（hi）循环单核细胞的消耗减少了肺纤维化（P = 0.0052）和Ym 1阳性交替激活的肺巨噬细胞的数量（P = 0.0310）。他们的过继转移过程中纤维化加剧（P 0.0304），然而，过继转移的CD45.1 Ly 6C（hi）细胞没有发现在受体CD45.2 mice.Conclusions的肺：我们证明了循环单核细胞和肺巨噬细胞在肺纤维化的重要性，并强调交替激活的巨噬细胞表型的重要性。我们发现Ly 6C（hi）单核细胞促进了肺纤维化的进展，但此后并没有明显地移入肺中。最后，我们提供的经验数据表明，巨噬细胞可能有一个解决促进作用，在可逆阶段的博莱霉素诱导的肺纤维化。
Rationale: Idiopathic pulmonary fibrosis (IPF) is a devastating disease. Antiinflammatory therapies, including corticosteroids, are of no benefit. The role of monocytes and macrophages is therefore controversial.Objectives: To define the role of monocytes and macrophages during lung fibrogenesis and resolution, and explore the phenotype of the cells involved.Methods: We used multiple in vivo depletional strategies, backed up by adoptive transfer techniques. Further studies were performed on samples from patients with IPF.Measurements and Main Results: Depletion of lung macrophages during fibrogenesis reduced pulmonary fibrosis as measured by lung collagen (P = 0.0079); fibrosis score (P = 0.0051); and quantitative polymerase chain reaction for surrogate markers of fibrosis Col1 (P = 0.0083) and alpha-smooth muscle actin (P = 0.0349). There was an associated reduction in markers of the profibrotic alternative macrophage activation phenotype, Ym1 (P = 0.0179), and Arginase1. The alternative macrophage marker CD163 was expressed on lung macrophages from patients with IPF. Depletion of Ly6C(hi) circulating monocytes reduced pulmonary fibrosis (P = 0.0052) and the number of Ym1-positive alternatively activated lung macrophages (P = 0.0310). Their adoptive transfer during fibrogenesis exacerbated fibrosis (P 0.0304); however, adoptively transferred CD45.1 Ly6C(hi) cells were not found in the lungs of recipient CD45.2 mice.Conclusions: We demonstrate the importance of circulating monocytes and lung macrophages during pulmonary fibrosis, and emphasize the importance of the alternatively activated macrophage phenotype. We show that Ly6C(hi) monocytes facilitate the progression of pulmonary fibrosis, but are not obviously engrafted into lungs thereafter. Finally, we provide empirical data to suggest that macrophages may have a resolution-promoting role during the reversible phase of bleomycin-induced pulmonary fibrosis.